Improvement of Paracrine and Tissue Regenerative Functions of Mesenchymal Stem Cells via Nanostructure‐Mediated Localized Mild Photothermal Signals

ABSTRACT Wound healing is an obvious clinical concern that can be hindered by insufficient angiogenesis, inflammation, and cellular dysfunction. While mesenchymal stem cell (MSC)‐derived paracrine products rich in therapeutic nutrients and cytokines demonstrate potential for accelerating healing, precisely stimulating and enhancing MSC paracrine function within regenerative medicine are challenging problems to solve. Inspired by the “hot spring” effect, a remote‐controlled and wireless platform integrating two‐dimensional (2D) Ti 3 C 2 T x MXene nanosheets (NSs) with topological scaffolds was designed to accurately transmit localized mild photothermal signals (∼43°C) to cells for effectively improving the paracrine factors of adipose‐derived stem cells (ADSCs). Mechanistically, the near‐infrared (NIR)‐mediated localized mild photothermal signals induced heat shock protein 90 (HSP90) signaling to activate the PI3K/AKT pathway and the LATS1/2‐YAP/TEAD1 signaling axis, thus enhancing the paracrine function of ADSCs. The improved ADSC paracrine products strengthened the interlocking connections in the immune‐vascularization‐tissue regeneration niche, which effectively promoted skin regeneration in vivo. In summary, this study proposed a strategy that can be utilized for stem cell engineering and for improving MSC paracrine function via nanostructure‐mediated physical signals, which will provide a new perspective for improving MSC paracrine function.